The long range objective of this project is to elucidate the basic mechanisms of drug allergy in man and to apply current and new knowledge to the development of diagnostic methods and therapeutic approaches to the clinical problems which drug hypersensitivity pose. The prototype chosen for study is penicillin hypersensitivity, the most prevalent drug allergy. Our previous work has supported the usefulness of skin testing with penicillin derivatives for the prediction of risk of immediate and accelerated reactions to penicillins. We have developed a radioallergosorbent test (RAST), and a radioimmuno-precipitation assay which now allows sensitive measurement of allergen-specific IgE and IgG antibodies in human serum. The RAST assay gives equivalent results to skin testing with penicilloyl polylysine. These in vitro assays will be applied to studies of the immune response to penicillin in patients receiving penicillin therapeutically. Study protocols will investigate the influence of duration and intensity of therapy, immunological status, and other clinical variables which may be important in the induction of anti-penicillin IgE antibody. Similar studies of the IgE and IgG immune response to insulin will be studied in insulin-dependent patients. The ultimate goal of this work is the identification of risk factors associated with the development of drug allergy, and better understanding of protective mechanisms which may prevent clinical reactivity. We also propose to pursue the development of a RAST assay for detection of IgE penicillin antibody of minor determinant specificity. The eventual aim is to provide in vitro serum assays which could be substituted entirely for penicillin skin tests, thereby facilitating screening for penicillin allergy and minimizing risk to the drug-sensitive patients. The serological tests for drug-specific antibodies will be used to study two additional areas of interest: (a) the cross-reactivity among the penicillins and the cephalosporins; and (b) the mechanisms of "desensitization" to penicillin and insulin in sensitive patients.